Download PDF
Synthesis 2018; 50(20): 4124-4132
DOI: 10.1055/s-0037-1610211
paper
© Georg Thieme Verlag Stuttgart · New York

Improved Synthesis of Anxiolytic, Anticonvulsant, and Antinociceptive α2/α3-GABA(A)-ergic Receptor Subtype Selective Ligands as Promising Agents to Treat Anxiety, Epilepsy, and Neuropathic Pain

Guanguan Li 
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA   Email: capncook@uwm.edu
,
Lalit K. Golani
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA   Email: capncook@uwm.edu
,
Rajwana Jahan
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA   Email: capncook@uwm.edu
,
Farjana Rashid
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA   Email: capncook@uwm.edu
,
James M. Cook*
Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA   Email: capncook@uwm.edu
› Author AffiliationsWe would like to thank the NIH for generous financial support (MH096463, NS076517).
Further Information

Publication History

Received: 04 June 2018

Accepted after revision: 06 June 2018

Publication Date:
24 July 2018 (online)

    Permissions and Reprints All articles of this category


Abstract

An improved synthesis of the anxiolytic, anticonvulsant, and antinociceptive compounds: Hz-166, and its bioisosteres 1,2,4-oxadiazole (MP-III-080) and 1,3-oxazole (KRM-II-81) were synthesized in higher yields and with more facile purification methods (crystallization, etc.) in multigram quantities without column chromatography. In the synthesis of KRM-II-81, an alternative procedure was employed using the selective reducing reagent, potassium diisobutyl-tert-butoxyaluminum hydride (PDBBA), to prepare the desired C(3)-aldehyde in the absence of N(5)–C(6) imine reduction in good yield on a 20 gram scale.

Key words

GABAAR - benzodiazepines - anxiety - epilepsy - neuropathic pain - large scale - imine - selective reduction

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1610211.
  • Supporting Information
 

  • References

  • 1 Richter L. de Graaf C. Sieghart W. Varagic Z. Morzinger M. de Esch IJ. Ecker GF. Ernst M. Nat. Chem. Biol. 2012; 8: 455
    CrossrefPubMed
  • 2 Rudolph U. Mohler H. Curr. Opin. Pharmacol. 2006; 6: 18
    CrossrefPubMed
  • 3 Clayton T. Chen JL. Ernst M. Richter L. Cromer BA. Morton CJ. Ng H. Kaczorowski CC. Helmstetter FJ. Furtmuller R. Ecker G. Parker MW. Sieghart W. Cook JM. Curr. Med. Chem. 2007; 14: 2755
    CrossrefPubMed
  • 4 Rudolph U. Crestani F. Benke D. Brunig I. Benson JA. Fritschy JM. Martin JR. Bluethmann H. Mohler H. Nature 1999; 401: 796
    Crossref
  • 5 Low K. Crestani F. Keist R. Benke D. Brunig I. Benson JA. Fritschy JM. Rulicke T. Bluethmann H. Mohler H. Rudolph U. Science 2000; 290: 131
    CrossrefPubMed
  • 6 Ninan PT. Insel TM. Cohen RM. Cook JM. Skolnick P. Paul SM. Science 1982; 218: 1332
    CrossrefPubMed
  • 7 Mendelson WB. Owen C. Skolnick P. Paul SM. Martin JV. Ko G. Wagner R. Sleep 1984; 7: 64
    CrossrefPubMed
  • 8 Cook JM. Huang Q. He X. Li X. Yu J. Han D. Lelas S. McElroy JF. US Patent US 7 119 196 B2, 2006
  • 9 Mirza NR. Larsen JS. Mathiasen C. Jacobsen TA. Munro G. Erichsen HK. Nielsen AN. Troelsen KB. Nielsen EO. Ahring PK. J. Pharmacol. Exp. Ther. 2008; 327: 954
    CrossrefPubMed
  • 10 Munro G. Lopez-Garcia JA. Rivera-Arconada I. Erichsen HK. Nielsen EO. Larsen JS. Ahring PK. Mirza NR. J. Pharmacol. Exp. Ther. 2008; 327: 969
    CrossrefPubMed
  • 11 Cook JM. Zhou H. Huang S. Sarma PV. V. S. Zhang C. US Patent US 7 618 958 B2, 2009
  • 12 Fischer BD. Licata SC. Edwankar RV. Wang ZJ. Huang S. He X. Yu J. Zhou H. Johnson EM. Jr. Cook JM. Furtmuller R. Ramerstorfer J. Sieghart W. Roth BL. Majumder S. Rowlett JK. Neuropharmacology 2010; 59: 612
    CrossrefPubMed
  • 13 Poe MM. Methuku KR. Li G. Verma AR. Teske KA. Stafford DC. Arnold LA. Cramer JW. Jones TM. Cerne R. Krambis MJ. Witkin JM. Jambrina E. Rehman S. Ernst M. Cook JM. Schkeryantz JM. J. Med. Chem. 2016; 59: 10800
    CrossrefPubMed
  • 14 Witkin JM. Cerne R. Wakulchik MS. J. Gleason SD. Jones TM. Li G. Arnold LA. Li JX. Schkeryantz JM. Methuku KR. Cook JM. Poe MM. Pharmacol. Biochem. Behav. 2017; 157: 35
    CrossrefPubMed
  • 15 Fischer BD. Schlitt RJ. Hamade BZ. Rehman S. Ernst M. Poe MM. Li G. Kodali R. Arnold LA. Cook JM. Brain Res. Bull. 2017; 131: 62
    CrossrefPubMed
  • 16 Atack JR. Wafford KA. Street LJ. Dawson GR. Tye S. Van Laere K. Bormans G. Sanabria-Bohorquez SM. De Lepeleire I. de Hoon JN. Van Hecken A. Burns HD. McKernan RM. Murphy MG. Hargreaves RJ. J. Psychopharmacol. 2011; 25: 314
    CrossrefPubMed
  • 17 Clayton T. Poe MM. Rallapalli S. Biawat P. Savic MM. Rowlett JK. Gallos G. Emala CW. Kaczorowski CC. Stafford DC. Arnold LA. Cook JM. Int. J. Med. Chem. 2015; 430248
  • 18 Rivas FM. Stables JP. Murphree L. Edwankar RV. Edwankar CR. Huang S. Jain HD. Zhou H. Majumder S. Sankar S. Roth BL. Ramerstorfer J. Furtmüller R. Sieghart W. Cook JM. J. Med. Chem. 2009; 52: 1795
    CrossrefPubMed
  • 19 Di Lio A. Benke D. Besson M. Desmeules J. Daali Y. Wang ZJ. Edwankar R. Cook JM. Zeilhofer HU. Neuropharmacology 2011; 60: 626
    CrossrefPubMed
  • 20 Namjoshi OA. Wang Z.-j. Rallapalli SK. Johnson EM. Johnson Y.-T. Ng H. Ramerstorfer J. Varagic Z. Sieghart W. Majumder S. Roth BL. Rowlett JK. Cook JM. Bioorg. Med. Chem. 2013; 21: 93
    CrossrefPubMed
  • 21 Patani GA. LaVoie EJ. Chem. Rev. 1996; 96: 3147
    CrossrefPubMed
  • 22 Langmuir I. J. Am. Chem. Soc. 1919; 41: 1543
    Crossref
  • 23 Burger A. Prog. Drug Res. 1991; 37: 287
    PubMed
  • 24 Boström J. Hogner A. Llinàs A. Wellner E. Plowright AT. J. Med. Chem. 2012; 55: 1817
    CrossrefPubMed
  • 25 Cook J. Huang S. Edwankar R. Namjoshi OA. Wang ZJ. US Patent US 8 835 424 B2, 2014
  • 26 Cook J. Poe MM. Methuku KR. Li G. PCT Int. Appl. WO 2016/154031 A1, 2016; US Patent Appl. US 2018/0065967 A1, 2018
  • 27 Shimazaki T. Iijima M. Chaki S. Eur. J. Pharmacol. 2004; 501: 121
    CrossrefPubMed
  • 28 Lewter LA. Fisher JL. Siemian JN. Methuku KR. Poe MM. Cook JM. Li J.-X. ACS Chem. Neurosci. 2017; 8: 1305
    Crossref
  • 29 Yang J. Teng Y. Ara S. Rallapalli S. Cook JM. Synthesis 2009; 145687
  • 30 Shenming H. Synthesis of Optically Active Subtype Selective Benzodiazepine Receptor Ligands: Ph. D. Thesis. University of Wisconsin-Milwaukee; Milwaukee: 2007
    Google Scholar
  • 31 Fryer IR. Walser A. Eur. Pat. Appl EP 1985135770, 1985 ; Chem. Abstr. 1985, 103: 160545
  • 32 Fryer IR. Gu ZQ. Wang CG. J. Heterocycl. Chem. 1991; 28: 1661
    Crossref
  • 33 Watjen F. Baker R. Engelstoff M. Herbert R. MacLeod A. Knight A. Merchant K. Moseley J. Saunders J. J. Med. Chem. 1989; 32: 2282
    CrossrefPubMed
  • 34 Kayukova LA. Pharm. Chem. J. 2005; 39: 539
    Crossref
  • 35 Li G. Stephen MR. Kodali R. Zahn NM. Poe MM. Tiruveedhula VV. N. P. B. Huber AT. Schussman MK. Qualmann K. Panhans CM. Raddatz NJ. Baker DA. Prevot TD. Banasr M. Sibille E. Arnold LA. Cook JM. ARKIVOC 2018; (iv): 158
    PubMed
  • 36 Fylaktakidou KC. Hadjipavlou-Litina DJ. Litinas KE. Varella EA. Nicolaides DN. Curr. Pharm. Des. 2008; 14: 1001
    CrossrefPubMed
  • 37 Mussoni L. Poggi A. De Gaetano G. Donati MB. Br. J. Cancer 1978; 37: 126
    CrossrefPubMed
  • 38 Greenblatt DJ. Matlis R. Scavone JM. Blyden GT. Harmatz JS. Shader RI. Br. J. Clin. Pharmacol. 1985; 19: 373
    CrossrefPubMed
  • 39 Drach SV. Litvinovskaya RP. Khripach VA. Chem. Heterocycl. Compd. 2000; 36: 233
    Crossref
  • 40 Turchi IJ. Dewar MJ. S. Chem. Rev. 1975; 75: 389
    Crossref
  • 41 van Leusen AM. Hoogenboom BE. Siderius H. Tetrahedron Lett. 1972; 2369
  • 42 Chae MJ. Song JI. An DK. Bull. Korean Chem. Soc. 2007; 28: 2517
  • 43 Boussonnière A. Bénéteau R. Lebreton J. Dénès F. Eur. J. Org. Chem. 2013; 7853
  • 44 Zakharkin LI. Khorlina IM. Tetrahedron Lett. 1962; 619